TORPEDO-NL will be an investigator-initiated, academically sponsored, multicentre, open-label, randomized controlled trial (RCT).
Patients with high-risk pulmonary embolism (PE) require immediate reperfusion therapy on top of anticoagulation. The standard reperfusion treatment in these patients is full-dose systemic thrombolysis. This carries a significant risk of major bleeding (10-25%) and intracranial haemorrhage (ICH, 3%). Catheter-directed thrombectomy (CDT) is a promising alternative to systemic thrombolysis with a more direct effect on reducing pulmonary artery clot burden and very likely a better safety profile. Randomized trials evaluating the safety and efficacy of CDT in high-risk patients are currently unavailable. The investigators hypothesize that in high-risk PE patients, CDT is superior to the current standard of systemic thrombolysis in terms of mortality and adverse events, i.e., is associated with a lower composite incidence of all-cause mortality, treatment failure, major bleeding and all-cause stroke. The investigators also hypothesize that CDT will lead to a shorter length of stay (LOS) at the intensive care unit (ICU) and in-hospital, faster recovery, and better long-term quality of life (QoL).
Objective: To determine whether CDT in high-risk PE relative to systemic thrombolysis is:
* more effective and safer in terms of a reduction of the composite endpoint on all-cause mortality and adverse events defined as treatment failure, major bleeding and all-cause stroke at day 30 (primary outcome) * leads to a better Desirability of Outcome Ranking (DOOR) at day 7 * associated with a lower level of oxygen supplementation at 48 hours * associated with shorter length of stay (LOS) at the intensive care unit (ICU) and in the hospital * associated with better functional recovery as well as better patient-reported outcomes such as QoL at one year * cost-effective after a time horizon of one year
Adult patients with confirmed acute PE, i.e. contrast filling defect in a lobar or more proximal pulmonary artery on computed tomography pulmonary angiography (CTPA), and/or obstructive shock with echocardiographic confirmed dilatation of the right ventricle and a congested vena cava inferior, both with/without echocardiographic signs of clot in transit or deep vein thrombosis of the leg.
High risk for mortality, i.e.
post cardiac arrest (after temporary need for cardiopulmonary resuscitation), OR
obstructive shock (systolic blood pressure <90 mmHg and signs of end-organ hypoperfusion (e.g. elevated lactate levels >2 mmol/l) or the need for vasopressors (adrenalin or noradrenalin) to maintain an adequate blood pressure), OR
"Catastrophic PE", i.e. ongoing cardiac arrest and/or need for extracorporeal cardiopulmonary resuscitation (ECPR) and/or immediate indication for venoarterial extracorporeal membrane oxygenation (VA-ECMO) as judged by the responsible physician(s)
Glascow Coma Scale <8 following resuscitation for cardiac arrest
Alternative diagnosis than acute PE contributing largely to the acute hemodynamic and/or respiratory failure, e.g. sepsis, COPD GOLD 3 or 4, or known heart failure with NYHA Functional Classification of 4, as judged by the treating physician.
A known "do not admit to the ICU" or "do not resuscitate" directive
Parallel
Catheter-directed thrombectomy (CDT)
DeviceThe intervention consists of immediate thrombectomy (thrombectomy with any approved device) without systemic/locally administered thrombolysis. Thrombectomy is performed via jugular or femoral venous access according to the instructions for use for the particular device. The catheter is advanced over a preplaced guidewire across the right heart into the pulmonary arteries to the location of proximal thrombus. Procedural therapeutic anticoagulation with heparin is administered. After removal of the dilator, the thrombus is extracted by controlled volume aspiration through an aspiration catheter using a syringe or dedicated aspiration system, with multiple aspirations performed as needed. Procedural objectives will be clearly stated prior to the intervention and patient's clinical and hemodynamic status and residual thrombus will guide the investigators to determine when to terminate the procedure. Treatment success is defined as clear evidence of right ventricular recompensation.
thrombolysis therapy
DrugStandard reperfusion treatment for high-risk PE patients is thrombolytic therapy, typically consisting of Alteplase, Urokinase, or Tenecteplase, with the idea of accelerated fragmentation of the thrombus by lytic medication given systemically.
The composite incidence of the binary endpoints of all-cause mortality, treatment failure, major bleeding and all-cause stroke at day 30.
This outcome will be assessed using patient records or information provided by the treating physician. A detailed description of treatment failure is provided in outcome 3 of the secondary outcomes. Major bleeding is defined as Bleeding Academic Research Consortium (BARC)3b and BARC3c bleeding (=intracranial haemorrhage). Ischemic stroke is defined as any stroke (National Institutes of Health Stroke Scale ≥1). Unit of measure: incidence (number and percentage).
To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with a better survival.
This will be assessed using patient records or information provided by the treating physician. Unit of measure: incidence (number and percentage).
To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with a lower incidence of treatment failure.
Treatment failure in the first six hours after randomization is defined as life-threatening hemodynamic or respiratory deterioration. This deterioration is the clinical scenario if, after randomization, the patient develops overt cardiorespiratory instability over at least 15 minutes necessitating CPR, escalation of respiratory support, or ECMO. After these first six hours, treatment failure will also be defined by increasing dosages of cardiorespiratory support (e.g. oxygen, catecholamines), and lack of improvement. Lack of improvement is defined by the presence of at least one of the following criteria: i) an equal or rising SCAI SHOCK stage, ii) an equal or rising Fraction of Inspired Oxygen (FiO2) level to maintain adequate oxygen saturation (i.e. ≥ 92%), or iii) an equal or decreasing P/F ratio. Unit of measure: incidence (number and percentage).
To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with a lower incidence of all-cause mortality.
This will be assessed using patient records or information provided by the treating physician. Unit of measure: incidence (number and percentage).
To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with a lower incidence of all-cause stroke.
Ischemic stroke is defined as any stroke (National Institutes of Health Stroke Scale ≥1).This will be assessed using patient records or information provided by the treating physician. Unit of measure: incidence (number and percentage).
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Leiden University Medical Center
Lead sponsor
Dutch Heart Foundation
Collaborator
ZonMw: The Netherlands Organisation for Health Research and Development
Collaborator
Zorginstituut Nederland: The Health Care Insurance Board
Collaborator
